Detection of interleukin-1 in the cartilage of patients with osteoarthritis: a possible autocrine/paracrine role in pathogenesis

Towle, Christine A.; Hung, Han Hwa; Bonassar, Lawrence J.; Treadwell, Benjamin V.; Mangham, D. C.

doi:10.1016/s1063-4584(97)80008-8

Cited by 117 publications

(89 citation statements)

References 29 publications

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“…Biochemical evidence also supports the conclusion that the production of IL-1 by chondrocytes is strongly induced in OA. 115 These results complement those of Kuettner and associates 116,117 who compared the responses of paired samples of human knee and ankle cartilage to IL-1. Articular cartilage from the knee, a common site of OA, responded strongly to IL-1, whereas cartilage from the ankle, where OA is very rare, mounted only a poor response.…”

Section: Il-1 As a Target In Oa Gene Therapysupporting

confidence: 77%

Osteoarthritis gene therapy

et al. 2004

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Section: Il-1 As a Target In Oa Gene Therapysupporting

confidence: 77%

Osteoarthritis gene therapy

et al. 2004

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“…Cartilage-We and others observed previously that human OA-affected cartilage (but not normal cartilage) produced IL-1 in an autocrine fashion, which regulates the production of other inflammatory mediators (1,11,13,18). This regulation was also dependent on the concentration of the IL-1 antagonizing molecules, IL-1ra and IL-1RII, which can also exist in soluble forms together with sIL-1RI.…”

Section: Expression Of Il-1 Family Receptors In Humanmentioning

confidence: 87%

Reversal of Autocrine and Paracrine Effects of Interleukin 1 (IL-1) in Human Arthritis by Type II IL-1 Decoy Receptor

Attur¹,

Dave²,

Cipolletta³

et al. 2000

Journal of Biological Chemistry

118

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Interleukin 1 (IL-1), produced by both synovial cells and chondrocytes, plays a pivotal role in the pathogenesis of cartilage destruction in osteoarthritis (OA). We examined the specific expression and function of IL-1 receptor family-related genes in human joint tissues. Gene array analysis of human normal and OA-affected cartilage showed mRNA expression of IL-1 receptor accessory protein (IL-1RAcp) and IL-1 type I receptor (IL-1RI), but not IL-1 antagonist (IL-1ra) and IL-1 type II decoy receptor (IL-1RII). Similarly, human synovial and epithelial cells showed an absence of IL-1RII mRNA. Functional genomic analyses showed that soluble (s) IL-1RII, at picomolar concentrations, but not soluble TNF receptor:Fc, significantly inhibited IL-1␤-induced nitric oxide (NO) and/or prostaglandin E 2 production in chondrocytes, synovial and epithelial cells. In OA-affected cartilage, the IC 50 for inhibition of NO production by sIL-1RII was 2 log orders lower than that for sIL-1RI. Human chondrocytes that overexpressed IL-1RII were resistant to IL-1-induced IL-1␤ mRNA accumulation and inhibition of proteoglycan synthesis. In osteoarthritis, deficient expression by chondrocytes of innate regulators or antagonists of IL-1 such as IL-1ra and IL-1RII (soluble or membrane form) may allow the catabolic effects of IL-1 to proceed unopposed. The sensitivity of IL-1 action to inhibition by sIL-1RII has therapeutic implications that could be directed toward correcting this unfavorable tissue(s) dependent imbalance. Osteoarthritis (OA)1 is considered a non-inflammatory arthritis, characterized by a limited infiltration of neutrophils into the synovial space and, in general, an absence of the classical signs of inflammation. Chondrocytes embedded within articular cartilage that is avascular and aneural reside in a sequestered environment, perhaps more than other cell types, whereby cellular metabolism is regulated by an autocrine mechanism responsive to biomechanical and pericellular signals. Recent observations by this and other laboratories indicate that, despite the general absence of clinical signs of inflammation, chondrocytes derived from patients with OA, show superinduction of proinflammatory genes typically associated with the products of synovial tissues in rheumatoid arthritis, including nitric-oxide synthase, cyclooxygenase-2, TNF␣, IL-6, and IL-8. The spontaneous production of the corresponding gene products and inflammatory mediators promotes a catabolic state, which leads to progressive cartilage damage in OA (1-4). This intraarticular inflammatory response in OA-affected cartilage, which may be considered as an in situ "molecular inflammation," is partially dependent on autocrine IL-1␤ production, which induces and sustains an imbalance of cartilage homeostasis and extracellular matrix synthesis (5). The autocrine production of IL-1 in OA-affected cartilage is amplified by engagement of integrins such as ␣ 5 ␤ 1 by abnormally expressed extracellular matrix proteins, including proteolytic fragments of fibronectin (5, 6)...

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“…We and others have previously shown that human OA-affected cartilage releases various inflammatory cytokines (including IL-1␤) that act in an autocrine fashion to affect chondrocyte functions (16,22,40). In view of these observations, the possibility that the integrins may act cooperatively with IL-1R to amplify the effects of IL-1␤ cannot be ruled out.…”

Section: Up-regulation Of No Pge 2 Il-6 Il-8 and Il-1␤ By Anti-␣mentioning

confidence: 99%

Functional Genomic Analysis in Arthritis-Affected Cartilage: Yin-Yang Regulation of Inflammatory Mediators by α5β1 and αVβ3 Integrins

Attur

Dave

Clancy

et al. 2000

The Journal of Immunology

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Osteoarthritis-affected cartilage exhibits enhanced expression of fibronectin (FN) and osteopontin (OPN) mRNA in differential display and bioinformatics screen. Functional genomic analysis shows that the engagement of the integrin receptors α5β1 and αvβ3 of FN and OPN, respectively, have profound effects on chondrocyte functions. Ligation of α5β1 using activating mAb JBS5 (which acts as agonist similar to FN N-terminal fragment) up-regulates the inflammatory mediators such as NO and PGE2 as well as the cytokines, IL-6 and IL-8. Furthermore, up-regulation of these proinflammatory mediators by α5β1 integrin ligation is mediated via induction and autocrine production of IL-1β, because type II soluble IL-1 decoy receptor inhibits their production. In contrast, αvβ3 complex-specific function-blocking mAb (LM609), which acts as an agonist similar to OPN, attenuates the production of IL-1β, NO, and PGE2 (triggered by α5β1, IL-1β, IL-18, or IL-1β, TNF-α, plus LPS) in a dominant negative fashion by osteoarthritis-affected cartilage and activated bovine chondrocytes. These data demonstrate a cross-talk in signaling mechanisms among integrins and show that integrin-mediated “outside in” and “inside out” signaling very likely influences cartilage homeostasis, and its deregulation may play a role in the pathogenesis of osteoarthritis.

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Detection of interleukin-1 in the cartilage of patients with osteoarthritis: a possible autocrine/paracrine role in pathogenesis

Cited by 117 publications

References 29 publications

Osteoarthritis gene therapy

Osteoarthritis gene therapy

Reversal of Autocrine and Paracrine Effects of Interleukin 1 (IL-1) in Human Arthritis by Type II IL-1 Decoy Receptor

Functional Genomic Analysis in Arthritis-Affected Cartilage: Yin-Yang Regulation of Inflammatory Mediators by α5β1 and αVβ3 Integrins

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